The intracellular second messenger CAMP is involved in relaxation of airway smooth muscles and regulation of the functions of inflammatory cells. CAMP is broken down by phosphodiesterase (PDE) and becomes inactive 5'-AMP. It is considered that an increase in concentration of cAMP due to suppression of cAMP metabolism by PDE would give bronchodilating and anti-inflammatory actions and would exhibit a therapeutic effect on inflammatory diseases such as asthma [Eur. Respir. J., 7, 579 (1994)]. Up to now, PDE has been classified into five types of isozymes (i.e., types I to V PDE). Their distributions differ among tissues [Trends Pharmacol. Sci., 12, 19 (1991)]. This suggests a possibility that selective inhibitors of PDE isozymes would result in tissue specific increase of intracellular CAMP concentration.
It is reported that a specific inhibitor of type IV PDE isozyme suppresses inflammatory cells functions [Thorax, 46, 512 (1991)] and is useful for inflammatory diseases such as asthma [J. Pharmacol. Exp. Ther., 266, 306 (1993)] and dermatitis [Br. J. Pharmacol., 112, 332 (1994)] and autoimmune diseases such as multiple sclerosis [Nature Medicine, 1, 244 (1994)] and rheumatoid arthritis [Clin. Exp. Immunol., 100, 126 (1995)]. In addition, it is thought that cardiovascular side effect caused by non-selective PDE inhibitors such as theophylline could be reduced by using selective type IV PDE inhibitor. Rolipram of the following formula (Japanese Unexamined Patent Publication (Kokai) No. 50-157360) is known as a compound having a specific inhibitory activity against type IV PDE. ##STR2##
Other compounds having a specific inhibitory activity against type IV PDE are known (W094/10118, W094/12461, Japanese Unexamined Patent Publication (Kokai) No. 5-117239, Japanese Unexamined Patent Publication (Kokai) No. 7-101861, WO95/03794, WO95/08534, etc.), but they have not been clinically applied up to now. Development of more useful compounds is desirable.
A compound having the formula (IV): ##STR3##
wherein R represents a hydrogen atom or a methyl group has been known [Tetrahedron Letter5, 25, 5023(1984)], but there is no description regarding the physiological activity of this compound. Japanese Unexamined Patent Publication (Kokai) No. 49-85050 describes that the compound having formula (V): ##STR4##
has a pharmacological action against an analgesic, sedative, antipyretic, ataractic, anticonvulsive, and other pharmacological actions against the central never system and a hypoglycemic, but does not describe a PDE IV inhibitory activity.